Multicenter, Randomized Trial in Newly Diagnosed Multiple Myeloma Patients Older Than 65 Years (GEM05>65)

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1 Multicenter, Randomized Trial in Newly Diagnosed Multiple Myeloma Patients Older Than 65 Years (GEM05>65) MV Mateos, A Oriol, J Martínez, MT Cibeira, R de Paz, MJ Terol, J García-Laraña, E Bengoechea, R Martínez, A Martín, F de Arriba, L Palomera, JM Hernández, JL Bello, ML Martín, Y González, JJ Lahuerta, J Bladé, JF San Miguel. On behalf of Spanish Myeloma Group (PETHEMA/GEM) 1

2 Multicenter, Two-stage Randomized Trial in Newly Diagnosed MM Patients Older Than 65 Years Induction Bort/Mel/Pred (VMP) vs Bort/Thal/Pred (VTP) Maintenance Bort/Thal (VT) Bort/Pred (VP) Bort/Thal (VT) Bort/Pred (VP) 2

3 Efficacy: Response Rate After Induction Therapy ITT analysis in 260 patients 60% 50% 40% ORR: 80% vs 81% 48% 46% VMP VTP 30% 27% 20% 10% 20% 12% 10% 10% 6% 11% 8% 0% CRIF- CRIF+ PR MR SD Only 2 pts in each arm progressed during induction *EBMT criteria Responses to VMP/VTP were rapid: Median time to achieve first response: 1.6 m Prolonged therapy improves the quality of response: Median time to achieve CR: VMP: 4.4 / VTP: 4.9 m 3

4 VMP vs VTP: Toxicity Profile (G3-4 AEs) (n=260) VMP (n:130) VTP (n:130) Hematologic toxicity - Anemia 15 (11%) 10 (8%) pns - Neutropenia 51 (39%) 29 (22%) p=0,008 - Thrombocytopenia 35 (27%) 16 (12%) p=0,0001 Non-hematologic toxicity - GI toxicities 9 (7%) 2 (2%) pns - PN 9 (5%) 12 (9%) pns - Infections 9 (7%) 1 (<1%) p=0,01 - DVT/Thromboembolism 1(<1%) 3 (2%) pns - Cardiologic events* - 11 (8%) p=0,001 Pts discontinuing due to SAEs, n (%) 15 (11%) 22 (17%) p=0,03 Deaths, n (%) 7* (5%) 7** (5%) p NS *5/7 in VMP: infections **5/7 in VTP: cardiac complications 4

5 VP vs VT: Toxicity Profile (AEs) (n=178) VP (n:87) VT (n:91) Hematologic toxicity (G1-2) - Anemia 2 (2%) 2 (2%) - Neutropenia 1 (1%) 3 (3%) - Thrombocytopenia 1 (1%) 1 (1%) Non-hematologic toxicity ( G3-4) - GI toxicities 1 (1%) 4 (4%) - PN 2 (2%) 5 (5%) - Infections 1 (1%) 2 (2%) -DVT/Thromboembolism - 1 (1%) - Cardiologic events* 1 (1%) 2 (2%) Patients discontinuing due to related-aes 4 + (5%) 7 ++ (7%) Deaths 1 (1%) 1 (1%) 5

6 Efficacy: Response Rate to Maintenance Therapy (n=178) CR (IF-) increased from 23% (after induction) up to 42% (maintenance) CR/nCR: 59% vs 55% 60% 50% 40% 44% 39% 44% 39% VT VP =91 =87 30% 20% 10% 0% 15% 16% 2% 1% CRIF- CRIF+ PR MR *EBMT criteria 6

7 Outcome of the Four Different Cohorts (n=178) 1,0 PFS 1,0 OS 0,8 Treat Group VMP-VT 0,8 0,6 VMP-VP 0,6 VTP-VT 0,4 VTP-VP 0,4 0,2 0,0 VMP+VT: NR VMP+VP: 32 m VTP+VT : NR VTP+VP :26.5 m VTP+VP vs VMP+VT HR 1.6, p= ,2 0,0 VMP+VT: 88% at 2y VMP+VP: 88% at 2y VTP+VT : 84% at 2y VTP+VP : 81% at 2y Cox regression analysis of PFS and OS with inverse probability weighting (p=0.8 for the interaction term) 7

8 Efficacy in High-Risk Cytogenetic Abnormalities 1,0 From 1st randomization From 2nd randomization PFS 1,0 PFS 0,8 0,8 0,6 0,6 0,4 0,4 0,2 0,0 0 5 Standard risk: 55% at 2 y High-risk: 58% at 2 y ,2 0,0 0 Standard risk: 61% at 2 y High-risk: 58% at 2 y ,0 OS 1,0 OS 0,8 0,8 0,6 0,6 0,4 0,4 0,2 Standard risk: 77% at 2 y High-risk: 74% at 2 y 0,2 Standard risk: 84% at 2 y High-risk: 82% at 2 y 0, ,

9 GIMEMA: Italian Multiple Myeloma Network Bortezomib, Melphalan, Prednisone and Thalidomide (VMPT) followed by maintenance with Bortezomib and Thalidomide (VT) for initial treatment of elderly multiple myeloma patients A. Palumbo 1, S. Bringhen 1, D. Rossi 2, R. Ria 2, M. Offidani 2, F. Patriarca 2, C. Nozzoli 2, A. Levi 2, T. Guglielmelli 2, G. Benevolo 2, V. Callea 2, B. Olivero 2, F. Morabito 2, M. Grasso 2, R. Marasca 2, M. Rizzo 2, A. Falcone 2, D. Gottardi 2, V. Montefusco 2, C. Musolino 2, R. Zambello 2, C. Cangialosi 2, G. Pietrantuono 2, V. Magarotto 1, M.T. Petrucci 2, P. Musto 2, G. Ciccone, F 2. Di Raimondo 2, G. Gaidano 2 and M. Boccadoro 1. 1 Division of Hematology, University of Torino, Torino, I, EU; 2 Italian Multiple Myeloma Network, GIMEMA, Italy. 9

10 Treatment Schedule 511 patients (older than 65 years) randomized from 58 Italian centers Patients: Symptomatic multiple myeloma/end organ damage with measurable disease 65 yrs or <65 yrs and not transplant-eligible; creatinine 2.5 mg/dl R A N D O M I Z E VMP Cycles 1-9 Bortezomib 1.3 mg/m 2 IV: days 1,8,15,22* Melphalan 9 mg/m 2 and prednisone 60 mg/m 2 days x 5-week cycles in both arms VMPT Cycles 1-9 Bortezomib 1.3 mg/m 2 IV: days 1,8,15,22* Melphalan 9 mg/m 2 and prednisone 60 mg/m 2 days 1-4 Thalidomide 50 mg/day continuously NO MAINTENANCE Until relapse MAINTENANCE Bortezomib 1.3 mg/m 2 IV: days 1,15 Thalidomide 50 mg/day continuously * 66 VMP patients and 73 VMPT patients were treated with twice weekly infusions of Bortezomib 10

11 Best Response Rate VMP (N=253) VMPT VT (N=250) P value CR 24% 38% > VGPR 50% 59% 0.03 > PR 81% 89% 0.01 % of patients CR VGPR PR VMP SD 1 PD % of patients CR 21 VGPR 30 VMPT VT PR 6 SD 1 PD 11

12 Time to Next Therapy Progression Free Survival Median follow-up 21.6 months Time to next therapy Progression free survival % of patients P = VMPT VT VMP VMPT VT: 3 years = 75% VMP: 3 years = 60% VMPT VT VMP VMPT VT: 3 years = 60% VMP: 3 years = 42% P = Months Months 12

13 Efficacy and Toxicity by Bortezomib Schedule VMP* (VISTA) VMP twice weekly N=63 VMP once weekly N=190 CR 30% 25% 23% 2 years 48% 56% 58% Sensory PN Any grade 44% 43% 21% Grade % 14% 2% PN discontinuation NA 16% 4% Total planned dose mg/m mg/m 2 Total delivered dose NA 41 mg/m 2 40 mg/m 2 *San Miguel JF et al. New Eng J Med 2008; 359: ; 3 patients in twice weekly and 1 patient in once weekly group are not evaluable because they never start therapy PN: peripheral neuropathy 13

14 Conclusion VMP (N=253) VMPT VT (N=250) P value CR 24% 38% years 60% 75% years 42% 60% years 89% 89%

15 A Phase III Study to Determine the Efficacy and Safety of Lenalidomide in Combination With Melphalan and Prednisone Followed by Lenalidomide (MPR-R) in Patients 65 Years With Newly Diagnosed Multiple Myeloma (NDMM) Antonio Palumbo 1, Meletios Dimopoulos 2, Michel Delforge 3, Martin Kropff 4, Robin Foa 5, Zhinuan Yu 6, Lindsay Herbein 6, Jay Mei 6, Christian Jacques 6, John Catalano 7 1 Division of Hematology, University of Torino, Torino, Italy; 2 Department of Clinical Therapeutics, Alexandra Hospital, University of Athens School of Medicine, Athens, Greece; 3 University Hospital Leuven, Leuven, Belgium; 4 Department of Medicine (Hematology/Oncology), University of Muenster, Muenster, Germany; 5 Division of Hematology, University, Rome, Italy; 6 Celgene Corporation, Summit, NJ; 7 Haematology Dept and Dorevitch Pathology, Frankston Hospital, Frankston, Australia 15

16 Phase III Study Schema N=459, 82 centers in Europe, Australia and Israel Cycles (28-day) 1-9 Cycles 10+ RANDOMISATION MPR-R M: 0.18 mg/kg, days 1-4 P: 2 mg/kg, days 1-4 R: 10 mg/day po, days 1-21 MPR M: Primary 0.18 mg/kg, Comparison days 1-4 P: 2 mg/kg, MPR-R days vs. 1-4 MP R: 10 mg/day po, days 1-21 Secondary MP Comparison M: 0.18 MPR-R mg/kg, vs. days MPR1-4 P: Addition 2 mg/kg, of days MPR 1-4 arm per PBO: days EMEA 1-21 advice Lenalidomide Continued Tx 10 mg/day, days 1-21 Placebo Placebo Disease progression Lenalidomide (25 mg/day) +/- dexamethasone Double-Blind Treatment Phase Open-Label Extension/ Follow-Up Phase Stratified by age ( 75 vs. > 75 years) and stage (ISS 1,2 vs. 3) M, melphalan; P, prednisone; R, lenalidomide; PBO, placebo. 16

17 Best Response Best Overall Response a MPR-R N = 152 MPR N = 153 MP N = 154 P Value (MPR-R vs. MP) ORR 77% 67% 49% <0.001 CR b 18% 13% 5% <0.001 VGPR c 32% 33% 11% <0.001 PR 45% 34% 37% --- Progressive Disease 0% 1% 0% --- Median time to first response, months <0.001 a. As measured using EBMT criteria 1 b. Immunofixation negative with or without bone marrow confirmation c. VGPR: >90% reduction in M-protein 1. Bladé J et al. Br J Haematol. 1998;102:

18 Patients without Event (%) Progression-Free Survival First Interim Analysis 50% Reduced Risk in PFS HR % CI [0.330, 0.755] Logrank P<0.001 MPR-R PFS Time (months) MP Median PFS Not reached 13.0 months Median follow up: 9.4 mos No. at Risk MPR-R MP

19 MPR-R vs MPR 47% Reduced Risk in PFS Patients without Event (%) No. at Risk HR % CI [0.350, 0.802] Logrank P= MPR-R MPR PFS Time (months) MPR-R MPR Median PFS Not reached 13.2 months 19

20 Lenalidomide, Bortezomib, Pegylated Liposomal Doxorubicin and Dexamethasone in Newly Diagnosed Myeloma: Updated Results of Phase I/II MMRC Trial A. J. Jakubowiak 1, D. Reece 2, C.C. Hofmeister 3, S. Lonial 4, T. Zimmerman 5, E. Campagnaro 1, R. Schlossman 6, J. Laubach 6, N. S. Raje 7, T. Anderson 1, K. Griffith 1, M. Hill 1, C. Harvey 1, A. Dollard 6, S. Wear 8, T. Bock 9, C. Tendler 10, D-L. Esseltine 11, S.L. Kelley 8, M. Kaminski 1, K.C. Anderson 6, and P. Richardson 6 1 University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, 2 Princess Margaret Hospital, Toronto, ON, 3 Ohio State University, Columbus, OH, 4 Winship Cancer Institute, Atlanta, GA, 5 University of Chicago Medical Center, Chicago, IL, 6 Dana-Farber Cancer Institute, Boston, MA, 7 Massechusettts General Hospital, Boston, MA, 8 Multiple Myeloma Reserarch Consortium, Narwalk, CT, 9 Celgene, Inc, Summit, NJ, 10 Centocor Ortho Biotech, Bridgewater, NJ, 11 Millennium Pharmaceuticals, The Takeda Oncology Company, Cambridge. MA 20

21 Treatment Schema Initial Treatment: Dose escalation of Len and PLD: up to eight 21-day cycles Bz Bz Bz Bz Dex Dex Dex Dex Dex Dex Dex Dex PLD Len Maintenance: 21-day cycles up to progression or toxicity Bz Dex Dex 21 Bz Dex Dex Len Dex, 20 mg/day days 1, 2, 4, 5, 8, 9, 11, and 12; 10 mg, cycles 5 8, and maintenance Pts PR may proceed to ASCT after 4 cycles Maintenance therapy permitted in pts SD after completion of 8 cycles DVT prophylaxis required with Lovenox or ASA 21

22 RVDD Induction followed by ASCT* Induction Post-Transplant % >VGPR 80 65% >VGPR 80 13% % % 20 42% 20 0 RVDD 0 RVDD VGPR CR/nCR VGPR CR/nCR *Actual transplant patients (N=26) 22

23 Novel Three- and Four-Drug Combinations of Bortezomib, Dexamethasone, Cyclophosphamide, and Lenalidomide, for Newly Diagnosed Multiple Myeloma: Results from the Multi-Center, Randomized, Phase 2 EVOLUTION Study Shaji Kumar, 1 Ian Flinn, 2 Parameswaran Hari, 3 Natalie Callander, 4 Stephen J Noga, 5 A Keith Stewart, 6 Jonathan Glass, 7 Noopur Raje, 8 Robert Rifkin, 9 Hongliang Shi, 10 Iain J Webb, 10 Paul G Richardson, 11 S Vincent Rajkumar 1 1 Division of Hematology, Mayo Clinic, Rochester, MN; 2 Sarah Cannon Research Institute, Nashville, TN; 3 Medical College of Wisconsin, Milwaukee, WI; 4 University of Wisconsin Comprehensive Cancer Center, Madison, WI; 5 Sinai Hospital of Baltimore, Baltimore, MD; 6 Mayo Clinic Arizona, Scottsdale, AZ; 7 Louisiana State University Health Sciences Center, Shreveport, LA; 8 Massachusetts General Hospital, Boston, MA; 9 Rocky Mountain Cancer Centers, Denver, CO; 10 Millennium Pharmaceuticals, Inc., Cambridge, MA; 11 Dana-Farber Cancer Institute, Boston, MA 23

24 Best response Response, % VDCR (N=41) VDR (N=42) VDC (N=32) VDC-mod (N=15) CR scr VGPR ncr VGPR (scr + CR + ncr + VGPR) ncr (scr+cr+ncr) PR Stable disease Progressive disease Patients categorized as VGPR include those who have no measurable M-protein but have not yet had bone marrow assessments to confirm CR/nCR status 24

25 Relapsed Options Carfilzomib Pomalidomide Elotuzomab HDAC inhibitors 25

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30 Pomalidomide (CC4047) plus low dose dexamethasone (Pom/dex) is active and well tolerated in lenalidomide refractory multiple myeloma (MM) M.Q.Lacy, MD, M. Gertz, MD, S. Hayman, K. Detweiler Short, A. Dispenzieri, S. Zeldenrust, S. Kumar, P. Greipp, J. Lust, S. Russell, F. Buadi, R. Kyle, R. Fonseca, L. Bergsagel, V. Roy, J. Mikhael, K. Stewart, J. Allred, K. Laumann, S. Mandrekar, S.V. Rajkumar Mayo Clinic Scottsdale, Arizona Rochester, Minnesota Jacksonville, Florida Mayo Clinic College of Medicine Mayo Clinic Comprehensive Cancer Center 30

31 Prior treatment Number of prior regimens (29%) (53%) 7+ 6 (18%) Median 4 Previous regimens Lenalidomide 34 (100%) Thalidomide 19 (58%) Bortezomib 20 (59%) Transplant 23 (68%) auto 23 allo 1 31

32 Response Rates Confirmed Response Rate 32% Best Response VGPR 1 (3%) PR 10 (29%) MR 6 (18%) SD 11 (32%) PD 6 (18%) 50% 32

33 A Phase 1/2 Multi-Center, Randomized, Open Label Dose Escalation Study to determine the Maximum Tolerated Dose, Safety, and Efficacy of Pomalidomide alone or in combination with low-dose Dexamethasone in Pts With Relapsed and Refractory Multiple Myeloma, who have been previously treated with Lenalidomide and Bortezomib; Preliminary Results Paul Richardson 1, David Siegel 2, Rachid Baz 3, Susan L Kelley 4, Nikhil C Munshi 1, Daniel Sullivan 3, Laura McBride 2, Deborah Doss 1, Gail Larkins 5, Christian Jacques 5, Arlene Donaldson 5, Kenneth C Anderson 1 1 Dana-Farber Cancer Institute, Boston, MA; 2 Hackensack University Medical Center, Hackensack, NJ; 3 H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; 4 Multiple Myeloma Research Consortium, Norwalk, CT; 5 Celgene Corporation, Summit, NJ 33

34 MM-002: Phase 1 Summary of Best Response POM Dose (± Dex) Best Response a 2 mg (n = 6) 1 PR, 1 SD, 1 PD, 3 NE 3 mg (n = 8) 1 CR, 1 MR, 5 SD, 1 NE 4 mg (n = 8) 2 PR, 3 MR, 1 SD, 2 NE 5 mg (n = 10) 3 PR, 2 MR, 3 SD, 1 PD, 1 NE CR, complete response; MR, minimal response; NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable disease. a. As measured using modified EBMT criteria 1,2 every 28d. 7/25 evaluable pts (28%) PR; 13/25 pts (52%) MR 3 15 pts received dex in addition to POM for either lack of response or PD; 8/15 pts (53%) improved response after dex added, with durability of response also improved from 13.5 to 16.9 wks 1. Bladé et al. Br J Haematol. 1998;102: Richardson et al. N Engl J Med. 2003;348(26): Anderson et al. Leukemia. 2008;22(2):

35 Phase 1/2 Study of Elotuzumab in Combination with Lenalidomide and Low Dose Dexamethasone in Relapsed or Refractory Multiple Myeloma: Interim Results Sagar Lonial 1, Ravi Vij 2, Jean-Luc Harousseau 3, Thierry Facon 4, Jonathan Kaufman 1, Amitabha Mazumder 5, Philippe Moreau 3, Xavier Leleu 4, John Fry 6, Anil Singhal 6 and Sundar Jagannath 5 1 Winship Cancer Institute, Emory University, Atlanta, GA; 2 Oncology, Washington University School of Medicine, Saint Louis, MO; 3 Hematology, CHU Hotel-Dieu, Nantes, France; 4 Service des maladies du sang, Hospital Claude Huriez, CHRU Lille, Lille, France; 5 St. Vincent's Comprehensive Cancer Center, New York, NY; 6 Facet Biotech, Redwood City, CA 35

36 Elotuzumab A humanized monoclonal IgG1 targeting CS1, a cell surface glycoprotein CS1 is highly and uniformly expressed on multiple myeloma cells, with restricted expression on NK cells and little to no expression on normal tissues Pre-clinical data indicates mechanism of action is mainly through NKmediated ADCC Elotuzumab monotherapy study in advanced MM patients exhibited a manageable safety profile (first dose infusion reactions were key AEs) and stable disease in a number of patients 20/20 bone marrow cores were positive for CS1 expression Hsi et al., Clin Cancer Res 14:2775,

37 Dosing Regimen DLT Observation Response Assessments Elotuzumab Dosing CYCLE 1 CYCLE 2 CYCLE 3 CYCLE 4 CYCLE N-1 5 CYCLE N6 Lenalidomide daily dose daily dose daily dose daily dose daily dose daily dose Cycle Day: Dexamethasone 3+3 dose escalation cohorts evaluating 5, 10, and 20 mg/kg elotuzumab in combination with 25 mg lenalidomide and low dose dexamethasone First 5 patients were limited to 6 cycles of treatment. Remaining 23 patients are being treated until disease progression or unacceptable toxicity, if earlier 37

38 Efficacy Best Confirmed Response Total Patients (%) Patients w/o prior lenalidomide Total treated population 1 ORR ( PR) 2 23 (82%) 21 (95%) VGPR 5 (18%) 5 (23%) PR 18 (64%) 16 (73%) SD 4 (14%) 1 (4%) PD 0 0 NE 1 (4%) 0 1 Patients receiving one or more doses of elotuzumab 2 Response assessed by IMWG criteria 38